It is estimated that more than a third of the world's human population (over 2 billion people) are infected with Mycobacterium tuberculosis (Mtb). One of the major hurdles to controlling the global spread of TB is the length of time required to effectively treat patients with active TB disease. It has been known for decades that humans infected with Mtb develop profound alterations in systemic glucose metabolism reflected by elevated blood glucose levels (hyperglycemia) and impaired glucose tolerance, which is restored to normal only after months of antimicrobial drug therapy. Moreover, TB patients also develop elevated serum free fatty acid levels (FFAs), which in a variety of non-TB diseases have been shown to be potent mediators of systemic insulin resistance. Since 1) altered fatty acid metabolism is directly linked to dysregulated glucose homeostasis and 2) systemic insulin resistance is the most common cause of impaired glucose tolerance, we will test the hypothesis that: Impaired glucose tolerance during Mtb infection is due to insulin resistance and that therapeutic restoration of systemic glucose homeostasis will slow TB disease progression and improve antimicrobial drug treatment responses. In these studies we will not only determine the molecular pathogenesis of altered glucose metabolism associated with active Mtb infection but also determine whether restoring metabolic homeostasis with antiglycemic drugs is beneficial as an adjunct to antimicrobial therapy. Our preliminary data show that, like humans, Mtb infected guinea pigs develop impaired glucose tolerance and elevated serum FFAs and that hyperglycemia exacerbates TB disease severity. In non-TB diseases like diabetes, it is well accepted that hyperglycemia is due to impaired glucose tolerance resulting from decreased sensitivity of certain tissues (skeletal muscle, liver and adipose tissue) to the activity of the pancreatic hormone insulin, which is referred to as insulin resistance. Based on these concepts we will use the guinea pig TB model to determine the molecular mechanisms of impaired glucose tolerance and whether restoring glucose homeostasis therapeutically alone or in combination with antimicrobial drugs, improves host responses to Mtb infection. In Aim 1, we will determine whether impaired glucose tolerance and the resulting hyperglycemia is due to systemic insulin resistance mediated by the subcellular distribution and accumulation of the lipid second messenger diacylglycerol (DAG). In Aim 2, we will determine whether restoring and maintaining systemic glucose homeostasis with FDA approved, antiglycemic drugs will slow TB disease progression in Mtb-infected guinea pigs. We will also determine whether the use of antiglycemic drugs, when combined with antimicrobial drugs, improves TB treatment responses. Collectively, these studies will determine whether the altered glucose metabolism observed during Mtb infection contributes to TB pathogenesis and if therapeutic restoration of metabolic homeostasis improves antimicrobial drug treatment responses. These studies address an urgent, unmet need for innovative strategies to improve current TB drug treatments.